The ability of cocaine to interact with a receptors provides a logical medications development target. Recent studies conclusively demonstrate that pharmacological antagonists or antisense oligonucleotides targeting sigma receptors prevent the convulsive, lethal, locomotor stimulant, and rewarding properties of cocaine in mice. Although these studies provide compelling evidence for sigma receptor antagonists as potential new medications for cocaine abuse, the mechanisms that underlie their ability to combat a wide array of behaviors are poorly understood. Therefore, to begin elucidating these protective mechanisms, a preliminary study combining behavioral pharmacological approaches with cDNA microarray analysis and RT-PCR confirmations were performed to identify changes in gene expression that are associated with the behavioral protective actions of BD1063, a prototypic a receptor antagonist. As a result of this preliminary study, we identified fra-2, an immediate early gene and member of the fos family of transcription factors, as an important mediator of the protective actions of BD1063 against cocaine. We propose that fra-2 related mechanisms are critically involved in the transition between the immediate response to cocaine and the more persistent changes that accompany repeated cocaine exposure. This hypothesized interaction between cocaine, a receptors, and fra-2 may explain the ability of a receptor antagonists to combat an array of behaviors following acute, as well as repeated, exposure to cocaine. To begin validating our hypothesis, the specific aims of this R21 are to: 1) determine the temporal relationship between cocaineinduced changes in fra-2 and CT receptor mRNA and protein expression, 2) identify the brain regions where cocaine-induced changes in Fra-2 and CT receptor expression occur, and 3) determine the temporal relationship between cocaine-induced increases in Fra-2 and cr receptor expression and the development of behavioral sensitization. Together, we anticipate that these studies will uncover new mechanisms that underlie the transition of the nervous system as it responds to acute vs. repeated cocaine exposures. Such information will be critical for developing novel therapies to combat cocaine abuse.